CoMMD3:Bmi1 fusion and COMMD3 protein regulate c-Myc transcription: Novel therapeutic target for metastatic prostate cancer

Syed Umbreen, Mudassir Meraj Banday, Anmbreen Jamroze, Adrian P. Mansini, Arsheed A. Ganaie, Marina G. Ferrari, Raihana Maqbool, Firdous H. Beigh, Paari Murugan, Colm Morrissey, Eva Corey, Badrinath R. Konety, Mohammad Saleem

Research output: Contribution to journalArticle

Abstract

Gene rearrangement is reported to be associated to the aggressive phenotype and poor prognosis in prostate cancer. We identified a gene fusion between a transcription repressor (BMI1) and transcriptional factor (COMMD3) in human prostate cancer. We show that COMMD3:BMI1 fusion expression is significantly increased in prostate cancer disease in an order: normal tissue < primary < metastatic tumors (Mets). Although elevated TMPRSS-ERG/ETV fusion is reported in prostate cancer, we identified a subtype of Mets exhibiting low TMPRSS:ETV and high COMMD3:BMI1. We delineated the mechanism and function of COMMD3 and COMMD3: BMI1 in prostate cancer. We show that COMMD3 level is elevated in prostate cancer cell models, PDX models (adeno-carcinoma, NECaP), and Mets. The analysis of TCGA/NIH/ GEO clinical data showed a positive correlation between increased COMMD3 expression to the disease recurrence and poor survival in prostate cancer. We show that COMMD3 drives proliferation of normal cells and promotes migration/ invasiveness of neoplastic cells. We show that COMMD3:BMI1 and COMMD3 regulate C-MYC transcription and C-MYC downstream pathway. The ChIP analysis showed that COMMD3 protein is recruited at the promoter of C-MYC gene. On the basis of these data, we investigated the relevance of COMMD3:BMI1 and COMMD3 as therapeutic targets using in vitro and xenograft mouse models. We show that siRNA-mediated targeting of COMMD3:BMI1 and COMMD3 significantly decreases (i) C-MYC expression in BRD/BET inhibitor–resistant cells, (ii) proliferation/invasion in vitro, and (iii) growth of prostate cancer cell tumors in mice. The IHC analysis of tumors confirmed the targeting of COMMD3-regulated molecular pathway under in vivo conditions. We conclude that COMMD3:BMI1 and COMMD3 are potential progression biomarkers and therapeutic targets of metastatic prostate cancer.

Original languageEnglish (US)
Pages (from-to)2111-2123
Number of pages13
JournalMolecular Cancer Therapeutics
Volume18
Issue number11
DOIs
StatePublished - Jan 1 2019

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PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

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